Although the occurrence of obesity and the development of type 2 diabetes mellitus are tightly intertwined, the biological mechanisms underlying this relationship are incompletely understood. The symptoms of diabetes-insulin resistance, relative insulin hyposecretion, and hyperglycemia-have been hypothesized by some to be caused by obesity. Others, however, had suggested just the opposite-that obesity is caused by the symptoms of diabetes. For example, a recent study suggested that insulin resistance might contribute to the development of obesity. Fruhbeck et al., Am J Physiol Endocrinol Metab, 280:E827–47, 2001.
Insight into the relationship between diabetes and obesity has been gained through research into adipose tissue physiology. Recent studies have shown that, in addition to storing triglycerides, adipose tissue functions as an active endocrine organ capable of secreting a variety of factors that affect whole-body energy homeostasis. These factors, collectively termed “adipocytokines” or “adipokines” (Matsuzawa et al., Ann NY Acad Sci, 892:146–54, 1999) include: leptin, tumor necrosis factor (TNF)-α (Hotamisligil, G S, J Intern Med, 245:621–5, 1999), plasminogen-activator inhibitor type 1 (PAI-1) (Shimomura et al., Nat Med, 2:800–3, 1996), adipsin (White et al., J Biol Chem, 267:9210–3, 1992), resistin (Steppan et al., Nature, 409:307–12, 2001) and adiponectin.
Adiponectin, also known as AdipoQ, apM1, GBP28 or Acrp30 (Scherer et al., J Biol Chem, 270:26746–9, 1995; Hu et al., J Biol Chem, 271:10697–703, 1996; Maeda et al., Biochem Biophys Res Commun, 221:286–9, 1996; and Nakano et al., J Biochem (Tokyo), 120:803–12, 1996), is a polypeptide consisting of an N-terminal collagenous domain and a C-terminal globular domain. Serum levels of adiponectin are significantly decreased in both obesity and type 2 diabetes, indicating a possible metabolic role or relationship to insulin resistance. Scherer et al., J Biol Chem, 270:26746–9, 1995; Arita et al., Biochem Biophys Res Commun, 257:79–83, 1999. Consistent with this, a recent report by Fruebis et al. (Proc Natl Acad Sci USA, 98:2005–10, 2001) implicated a proteolytic fragment of adiponectin as an acute stimulator of fatty-acid oxidation by muscle. Other recent reports showed a possible causal role of adiponectin in the development of insulin resistance. Fruebis et al., Proc Natl Acad Sci USA, 98:2005–10, 2001; Yamauchi et al., Nat Med, 7:941–6, 2001.
While the research into adipose tissue physiology has not yet rendered a clear and complete explanation of the mechanisms underlying the relationship between diabetes and obesity, it has provided several new avenues to explore for developing new treatments for these disorders. In fact, many prospective treatments involving modulation of adipokine levels have been attempted with mixed results.